Submissions for variant NM_000352.6(ABCC8):c.3545G>A (p.Arg1182Gln)

dbSNP: rs193922400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029257	SCV000051903	likely pathogenic	Neonatal diabetes mellitus	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Invitae	RCV001388602	SCV001589658	pathogenic	not provided	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 1182 of the ABCC8 protein (p.Arg1182Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with neonatal diabetes mellitus (PMID: 16885549, 17446535, 22749773, 24622368). This variant is also known as Arg1183Gln. ClinVar contains an entry for this variant (Variation ID: 35611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 22451668). For these reasons, this variant has been classified as Pathogenic.
PerkinElmer Genomics	RCV001388602	SCV002023927	likely pathogenic	not provided	2020-03-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000193953	SCV002070463	pathogenic	Diabetes mellitus, transient neonatal, 2	2019-06-17	no assertion criteria provided	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.3545G>A, in exon 28 that results in an amino acid change, p.Arg1182Gln. This sequence change has been previously described in patients with transient neonatal diabetes, in both the de novo (PMID: 17389331) and familial state (PMIDs: 16885549, 22749773). It was identified in a father of one patient who presented with type 2 diabetes occurring later in life which was treated with diet alone (PMID: 16885549). Another missense variant affecting the same amino acid residue, p.Arg1182Trp, has also been described in patients with neonatal diabetes presenting with severe hyperglycemia (Flanagan et al., 2007). This sequence change has not been described in the population databases such as ExAC and gnomAD (dbSNP rs193922400). The p.Arg1182Gln change affects a highly conserved amino acid residue located in a functional domain of the ABCC8 protein that is known to be functional.